Direct identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry

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Michal Bassani-Sternberg, Eva Bräunlein, Richard Klar, Thomas Engleitner, Pavel Sinitcyn, Stefan Audehm, Melanie Straub, Julia Weber, Julia Slotta-Huspenina, Katja Specht, Marc E Martignoni, Angelika Werner, Rüdiger Hein, Dirk H Busch, Christian Peschel, Roland Rad, Jürgen Cox, Matthias Mann, Angela M Krackhardt

Although mutations may represent attractive targets for immunotherapy, direct identification of mutated peptide ligands isolated from human leucocyte antigens (HLA) on the surface of native tumour tissue has so far not been successful. Using advanced mass spectrometry (MS) analysis, we survey the melanoma-associated immunopeptidome to a depth of 95,500 patient-presented peptides. We thereby discover a large spectrum of attractive target antigen candidates including cancer testis antigens and phosphopeptides. Most importantly, we identify peptide ligands presented on native tumour tissue samples harbouring somatic mutations. Four of eleven mutated ligands prove to be immunogenic by neoantigen-specific T-cell responses. Moreover, tumour-reactive T cells with specificity for selected neoantigens identified by MS are detected in the patient's tumour and peripheral blood. We conclude that direct identification of mutated peptide ligands from primary tumour material by MS is possible and yields true neoepitopes with high relevance for immunotherapeutic strategies in cancer.

Original languageEnglish
JournalNature Communications
Volume7
Pages (from-to)13404
ISSN2041-1723
DOIs
Publication statusPublished - 21 Nov 2016
Externally publishedYes

    Research areas

  • Journal Article

ID: 184324084